(a) Field of the Invention
The present invention relates to a semi-synthetic process for the preparation of paclitaxel, docetaxel, the anticancer drugs, and 10-deacetylbaccatin III, a useful precursor for making them, the most popular anticancer drugs, and other taxane compounds. More particularly, this invention relates to a novel semi-synthetic route to synthesize paclitaxel, docetaxel and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III, a taxane compound which is isolated from Taxus Canadensis, an evergreen bush found in Eastern Canada and Northeastern United States.
(b) Description of Prior Art
Taxanes are substances occurring naturally in yew trees such as Taxus brevifolia, Taxus baccata and Taxus canadensis, which is common in Eastern Canada and Northeast United States. One of the chemicals extracted from the needles of Taxus canadensis is 9-dihydro-13-acetylbaccatin III, which is used to produce 10-deacetylbaccatin III, a useful intermediate for the preparation of paclitaxel, docetaxel and their analogues thereof.
The taxane family of diterpenes is considered to be an exceptionally promising group of cancer chemotherapeutic agents. Many taxane derivatives, including paclitaxel, docetaxel, taxol C and cephalomannine are highly cytotoxic and possess strong in vivo activities in a number of leukemic and other tumor systems. Paclitaxel, and a number of its derivatives, have been shown to be effective against advanced breast and ovarian cancers in clinical trials. They have also exhibited promising activity against a number of other tumor types in preliminary investigations. Paclitaxel, docetaxel have recently been approved in the U.S. and Canada for the treatment of ovarian and breast cancers.
The only available natural source of paclitaxel to date are several species of a slow growing yew trees (genus Taxus), wherein paclitaxel is found in very low concentrations (less than 400 parts per million) in the bark or needles of these trees. Thus, paclitaxel can be isolated from the bark of the pacific yew tree (Taxus brevifolia) and ground hemlock (Taxus Canadensis), but the yield is very low (0.01%-0.02%), and the isolation and purification process is too complicate. Furthermore the extraction is difficult, and the process is expensive. Since removal of the bark destroys the trees and endangers the species, isolation of taxanes from the stems and needles of various Taxus species was believed to offer hope that the supply of taxanes, in particular paclitaxel, would become more abundant. This led to the switching of paclitaxel derived from natural to the production of semi-synthetic, starting from 10-deacetylbaccatin III, which was isolated from the needles of English yew (Taxus baccata).
Due to the structural complexity of paclitaxel, and docetaxel, partial synthesis is a far more viable approach to providing adequate supplies of paclitaxel and docetaxel. Docetaxel was first commercialized by Aventis, It went to the market in 1995 and it is a fast growing anticancer drug. This drug is semi-synthetic product, also starting from 10-deacetylbaccatin III. So far the commercial supply of docetaxel comes substantially completely from 10-deacetylbaccatin III. To date, however, the supply of 10-deacetylbaccatin III is limited due to the limited biomass resource and low isolation yield (ranging from 50-165 mg per kilogram of needles of Taxus baccata).
Various processes of converting 9-dihydro-13-acetylbaccatin III (9-DHAB) into 10-deacetylbaccatin III have been proposed. However, it has been found that such processes result in poor yields of final product. Thus, a need still exists for an efficient method for converting 9-dihydro-13-acetylbaccatin III to 10-deacetylbaccatin III (10-DAB III).
The preparation of paclitaxel derivatives, some of which have been reported to demonstrate enhanced chemotherapeutic activity, ultimately depends upon the supply of the precursor compound, namely, 10-deacetylbaccatin III (10-DAB III). The structure of 10-DAB III has the basic diterpenoid structure of paclitaxel without the acetyl group at C-10 and side chain at the C-13 position.
Since 10-DAB III is an important staring material in paclitaxel semi-synthesis, the significance of 10-DAB III will likely increase as more clinical studies are performed using paclitaxel. One such reason is that it appears that water-soluble paclitaxel-like compounds with slightly modified C-13 side chains may be more desirable as cancer chemotherapeutic agents than the naturally-occurring, less water soluble paclitaxel. This increases the urgent need for the production of 10-DAB III as a starting material to synthesize both paclitaxel and second or third generation paclitaxel-like compounds. There is, therefore, a need for an improved method of isolating and/or synthesizing 10-DAB III.
In fact, most of the research to date regarding the semi-synthesis of paclitaxel has involved 10-deacetylbaccatin III. The conversion of 10-deacetylbaccatin III into paclitaxel is typically achieved by protecting the hydroxy at C-7, attachment of an acetyl group at the C-10 position, attachment of a C-13 β-amido ester side chain at the C-13 position through esterification of the C-13 alcohol with the side chain moiety, and deprotecting C-7. Since the supply of 10-deacetylbaccatin III is limited, other sources should be pursued.
Canadian Patent Application No. 2,188,190, published on Apr. 18, 1998, in the name of Zamir et al, described a semi-synthetic process to convert a naturally occurring taxane, 9-dihydro-13-acetylbaccatin III, into a suitable starting material for the synthesis of such taxane derivatives as paclitaxel, cephelomanine and other taxanes, which are structurally related to baccatin III.
U.S. Pat. No. 6,812,356, issued on Nov. 2, 2004, in the name of Findly, provided a process for the use of 9-dihydro-13-acetylbaccatin III for the production of 10-deacetylbaccatin III.
U.S. Pat. No. 6,784,304, issued on Aug. 31, 2004, in the name of Bristol-Myers Squibb Company provided novel oxazolidines, which found utility as intermediates in the preparation of C-13 side chain-bearing taxanes, e.g., paclitaxel and analogs thereof. It related more specifically to procedures for coupling the oxazolidines to form taxanes.
U.S. Pat. No. 6,710,191, issued on Mar. 23, 2004 in the name of R. A. Holton et al, provided a process for the preparation of a derivative or analog of baccatin III, or 10-deacetylbaccatin III, having a C9 substituent other than a keto, in which the C9 keto substituent of taxol, a taxol analog, baccatin III, or 10-deacetylbaccatin III was selectively reduced to the corresponding hydroxyl group.
U.S. Pat. No. 6,593,482, issued on Jul. 15, 2003 in the name of H. Bouchard et al, provided a procedure for preparing methylthiomethyl taxoids from baccatin III and β-lactam.
U.S. Pat. No. 6,576,777, issued on Jun. 10, 2003 in the name of L. Zamir et al, provided a semi-synthetic process to convert a naturally occurring taxane into a suitable starting compound for the synthesis of paclitaxel and related compounds. It specifically related to a process for the conversion of 9-dihydro-13-acetylbaccatin III into a 7-protected baccatin III, which can be used for the synthesis of taxol derivatives, e.g., paclitaxel, docataxel, cephalomannine and other taxanes, which were structurally related to baccatin III.
Other patents which provided processes for the preparation of novel taxoids included U.S. Pat. No. 6,384,071 issued on May 7, 2002 in the name of Aventis Pharma S.A, U.S. Pat. No. 6,331,635 issued on Dec. 18, 2001, in the name of Aventis Pharma S.A. and U.S. Pat. No. 6,232,477 issued on May 15, 2001 in the name of Aventis Pharma S.A.
U.S. Pat. No. 6,222,053, issued on Apr. 24, 2001, in the name of Institut National de la Research Scientific, provided a semi-synthetic process to convert a naturally occurring taxane into a suitable starting material for the synthesis of paclitaxel and related compounds. Specifically, it related to a process for the conversion of 9-dihydro-13-acetylbaccatin III into a 7-protected baccatin III, which can then be used as starting material for the synthesis of such taxane derivatives as paclitaxel, docetaxel, cephalomannine and other taxanes structurally related to baccatin III.
U.S. Pat. No. 6,197,981, issued on Mar. 6, 2001, in the name of J. Liu, provided a process for preparing taxol, baccatin III and 10-deacetylbaccatin III by oxidation of 9-dihydro-13-acetylbaccatin.
U.S. Pat. No. 6,175,023, issued on Jan. 16, 2001 in the name of J. Liu, provided for the semi-synthesis of 9-dihydrotaxanes using 9-dihydro-13-acetylbaccatin III as the initial compound.
U.S. Pat. No. 6,066,747, issued on May 23, 2000 in the name of R. H. Holton et al, provided a process for the preparation of taxol, baccatin III and 10-deacetylbaccatin III derivatives or other taxanes having new C9 functional groups.
U.S. Pat. No. 5,616,740, issued on Apr. 1, 1997 in the name of Abbott Laboratories, U.S. Pat. No. 5,594,157, issued on Jan. 14, 1997 in the name of Abbott Laboratories and U.S. Pat. No. 5,530,020 issued on Jun. 25, 1996 in the name of Abbott Laboratories each provided deoxygenated taxol compounds which were prepared from a natural product, 9-dihydro-13-acetylbaccatin III, which was isolated from Taxus canadensis, as well as analogs of taxol which were prepared therefrom.
U.S. Pat. No. 5,440,056, issued on Aug. 8, 1995 in the name of Abbott Laboratories, provided deoxygenated taxol products prepared from a natural product, 9-dihydro-13-acetylbaccatin III, which is isolated from Taxus canadensis. 
U.S. Pat. No. 4,924,011, re-issued as U.S. Pat. No. 34,277 in the name of Denis et al provided the first successful semi-synthesis of paclitaxel using the starting material 10-deacetylbaccatin III which can be extracted in relatively high yield from the needles of Taxus baccata species.
It would be highly desirable to be provided with a novel semi-synthetic process for the preparation of paclitaxel, docetaxel, the anticancer drugs, and 10-deacetylbaccatin III, a useful precursor for making them, the most popular anticancer drugs, and other taxane compounds.